Although aging may reflect, in part, the outcome of environmental stresses on cells and tissues, a question of major interest is whether both environmental effects and inherent programmed deterioration contribute to biological senescence. The human diploid cell lines and the virus-transformed cultures derived from them provide an avenue of approach to this question. Cultures of the former have a finite life span in terms of the total number of successive generations they can undergo. The latter cells have an indeterminate life span. The subject of this proposal is the mechanism of control of senescence and cell proliferation. Our purpose is to understand how the generalized loss of regulatory capacity that is characteristic of the aging organism is expressed at the cellular and molecular level. We are interested in defining the successive procession of events making up the phenomenon of cellular senescence in terms of quantitative biochemical relationships. Our objective is to examine, in a systematic way, using young, old and transformed diploid cells, aspects of chromosome and gene mutation, transcription, translation, protein function, and the structure-function relationships of various organelles on life span. We will first describe, in molecular terms, the changes which occur, and then analyze the mechanisms underlying these changes.